Magnesium-substituted hydroxyapatites

ABSTRACT

A stable, phase-pure magnesium-substituted crystalline hydroxyapatite containing from about 2.0 to about 29 wt % magnesium, wherein at least 75 wt % of the magnesium content is substituted for calcium ions in the hydroxyapatite lattice structure.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to methods for magnesiumsubstitution of crystalline hydroxyapatites that provide heretoforeunobtained levels of magnesium incorporation into the hydroxyapatitelattice structure. The present invention also relates to phase-puremagnesium-substituted crystalline hydroxyapatites obtained thereby.

[0002] Hydroxyapatite (HAp, chemical formula Ca₁₀(PO₄)₆(OH)₂) hasattracted the attention of researchers over the past thirty years as animplant material because of its excellent biocompatibility andbioactivity. HAp has been extensively used in medicine for implantfabrication. It is commonly the material of choice for the fabricationof dense and porous bioceramics. Its general uses include biocompatiblephase-reinforcement in composites, coatings on metal implants andgranular fill for direct incorporation into human tissue. It has alsobeen extensively investigated for non-medical applications such as apacking material/support for column chromatography, gas sensors andcatalysts, as a host material for lasers, and as a plant growthsubstrate. All properties of HAp, including bioactivity,biocompatibility, solubility and adsorption properties can be tailoredwithin a wide range by controlling qualitatively and quantitatively theions substituted for Ca²⁺, PO₄ ⁻ and OH⁻ in the HAp lattice structure.

[0003] Magnesium has been known as one of the cationic substitutes forcalcium in the HAp lattice structure. Magnesium-substituted HAp can beexpressed by the simplified chemical formula:

Ca_(10-x)Mg_(x)(PO₄)₆(OH)₂

[0004] with x/10 representing atom-percent substitution of magnesiumions for calcium ions.

[0005] Magnesium is also one of the predominant substitutes for calciumin biological apatites. Enamel, dentin, and bone contain respectively0.44 wt %, 1.23 wt % and 0.72 wt % magnesium. Accordingly,magnesium-substituted HAp materials (Mg—HAp) are expected to haveexcellent biocompatibility and properties that can be favorably comparedwith those of hard tissue. U.S. Pat. No. 6,027,742 and WO 00/03747, forexample, disclose the use of Mg—HAp as bone substitutes and for dentalapplications, respectively.

[0006] Increasing concentration of MG in HAp has the following effectson its properties: (a) gradual decrease in crystallinity, (b) increaseHPO₄ incorporation, and (c) increase in extent of dissolution. Magnesiumis closely associated with mineralization of calcified tissues, andindirectly influences mineral metabolism. It has been suggested thatmagnesium directly stimulates osteoblast proliferation with an effectcomparable to that of insulin (a known growth factor for osteoblast).Thus, it becomes possible to tailor the physicochemical properties ofHAp, as well as its biocompatibility and bioactivity, by controlling theMg substitution of the HAp lattice structure.

[0007] Because the optimum amounts of magnesium in artificial HApceramics can vary with different applications, the capability to controlprecisely the amounts of magnesium in HAp in the widest possible rangeby controlling the synthesis procedure is of primary importance. Mg—HAppowders have been prepared by precipitation and hydrolysis methods withthe replacement of calcium by magnesium limited to no more than 0.3 wt%.

[0008] Bigi et al., J. Inorg. Biochem. 49, 69-78(1993) disclosed thesynthesis of crystalline Mg—HAp powders with up to about 30 atom-percent(about 7.5 wt %) of magnesium under hydrothermal conditions at 120° C.Above this level of magnesium substitution the product was reported tobe completely amorphous. At most, 7 atom-percent (about 1.7 wt %) ofmagnesium ions were reported to be capable of substitution for calciumin the HAp lattice structure.

[0009] A need exists for crystalline Mg—HAp powders with a highermagnesium content, a higher degree of magnesium-substitution in the HAplattice structure, as well as a simple and inexpensive synthesis ofMg—HAp.

SUMMARY OF THE INVENTION

[0010] This need is met by the present invention. It has now beendiscovered that hybrid mechanochemical-hydrothermal synthesis techniquesmay be employed to produce magnesium-substituted HAp with not onlyheretofore unobtained magnesium levels, but also with levels ofmagnesium incorporation into the HAp lattice structure that was notbelieved possible until now.

[0011] Mechanochemical powder synthesis is a solid-state synthesismethod that takes advantage of the perturbation of surface-bondedspecies by pressure to enhance thermodynamic and kinetic reactionsbetween solids. Pressure can be applied at room temperature by millingequipment ranging from low-energy ball mills to high-energy stirredmills. The main advantages of the mechanochemical synthesis of ceramicpowders are simplicity and low cost. Therefore, a variety of chemicalcompounds have been already prepared by this technique, for exampleCaSiO₃, PbTiO₃, and 0.9Pb(Mg_(⅓)Nb_(⅔)) O₃−0.1PbTiO₃, etc. Since themechanochemical synthesis involves only solid-state reactions, it isclearly distinguished from the mechanochemical-hydrothermal synthesis(sometimes called “wet” mechanochemical), which takes advantage of thepresence of an aqueous solution in the system. An aqueous solution canactively participate in the mechanochemical reaction by acceleration ofdissolution, diffusion, adsorption, reaction rate and crystallization(nucleation and growth). The mechanochemical activation of slurries cangenerate local zones of high temperatures (up to 450-700° C.) and highpressure due to friction effects and adiabatic heating of gas bubbles(if present in the slurry), while the overall temperature is close tothe room temperature.

[0012] The mechanochemical-hydrothermal technique is thus located at theintersection of hydrothermal and mechanochemical processing. Themechanochemical-hydrothermal route produces comparable amounts of HAppowder as the hydrothermal processing but it requires lower temperature,i.e., room temperature, as compared to typically 90-200° C. for thehydrothermal processing. Perhaps the biggest advantage of theroom-temperature mechanochemical-hydrothermal processing is that thereis no need for a pressure vessel and no need to heat the reactionmixture. The reaction is thus conducted either as a comminuting orstirred tank reaction process.

[0013] Therefore, according to one aspect of the present invention, astable, phase-pure magnesium-substituted crystalline hydroxyapatite isprovided containing from about 2.0 to about 29 wt % magnesium, whereinat least 75 wt % of the magnesium content is substituted for calciumions in the hydroxyapatite lattice structure. The Mg—HAp of the presentinvention forms as crystal agglomerates. The present invention thereforealso includes particles of the Mg—HAp of the present invention having aparticle size between about 5 mm and about 100 microns.

[0014] The high magnesium content and high degree of magnesiumsubstitution in the HAp lattice structure is attributable to thecombined use of mechanochemical and hydrothermal process steps.Therefore, according to another aspect of the present invention, amethod for the preparation of Mg—HAp is provided, which includes thestep of mechanochemically reacting in a stoichiometric ratio selected toprovide a predetermined level of magnesium substitution, a source ofcalcium ions, a source of magnesium ions, a source of phosphate ions anda source of hydroxide ions, at least one of which is soluble in water,in an aqueous reaction medium until Mg—HAp is formed. One material mayserve as a multiple ion source. For example, magnesium hydroxide may beemployed as a source of both magnesium and hydroxide ions, or calciumhydrogen phosphate may be employed as a source of calcium and phosphateions.

[0015] The preferred source of phosphate ions is diammonium hydrogenphosphate, which is highly water soluble. Hydroxides of calcium andmagnesium are preferred sources of these two cations. With magnesiumhydroxide, at higher levels of magnesium substitution, unreactedmagnesium hydroxide should be removed, preferably by washing the Mg—HApin ammonium citrate aqueous solution so that the unreacted magnesiumhydroxide preferentially dissolves therein.

[0016] The ammonium citrate washing step represents a novel approach toincreasing the level of hydroxyapatite lattice—incorporated magnesiumrelative to the total magnesium content, as well as relative to thelattice-incorporated calcium. Therefore, according to another aspect ofthe present invention, a method is provided for increasing the magnesiumcontent in the lattice structure of magnesium-substituted crystallinehydroxyapatite relative to the calcium content of the lattice structureand to the non-lattice magnesium content, in which themagnesium-substituted hydroxyapatite is washed with an aqueous ammoniumcitrate solution.

[0017] The Mg—HAp of the present invention more closely resemblesbiological apatites than conventional HAp ceramics. Therefore, accordingto another aspect of the present invention there is provided abiocompatible hard tissue implant containing the Mg—HAp of the presentinvention. For example, metal or polymeric hard tissue implants may becreated that are coated with the Mg—HAp of the present invention, aswell as implants that are formed from metal or polymeric Mg—HApcomposite materials. The present invention also includes a granular fillfor direct incorporation into human or animal tissues containing theMg—HAp of the present invention, as well as dentifrice compositions,such as toothpaste, metal or polymeric composites for filling dentalcavities, and bone cements containing the Mg—HAp of the presentinvention.

[0018] The easy to control stoichiometry makes the Mg—HAp of the presentinvention ideal for use as a packing material for chromatography columnsand gas sensors, as well as a support for catalytic materials or a plantgrowth substrate. Stoichiometric optimization can provide the end useproperties needed for each end-use application.

[0019] Therefore, accordingly to another aspect of the presentinvention, there is provided a packing material for use in achromatography column or gas sensor, or as a support for a catalyticmaterial, containing the Mg—HAp of the present invention. The presentinvention also provides host materials for luminescent applicationscontaining the Mg—HAp of the present invention, as well as plant growthsubstrates containing the Mg—HAp of the present invention.

[0020] The present invention thus provides a means by which levels ofmagnesium substitution in HAp may be controlled by changing the ratio ofcalcium and magnesium ions in the source materials to tailor theend-product to specific end-use applications. The foregoing and otherobjects, features, and advantages of the present invention are morereadily apparent from the detailed description of the preferredembodiments set forth below.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] The magnesium-substituted hydroxyapatites of the presentinvention are prepared by a combined mechanochemical-hydrothermalprocess. A source of magnesium ions, a source of calcium ions, a sourceof phosphate ions and a source of hydroxide ions are mechanochemicallyreacted in an aqueous reaction medium. At least one ion source iswater-soluble.

[0022] For purposes of the present invention, “water-soluble” ionsources are defined as being materials having a solubility in water ofat least about 2.0 g/L. A solubility greater than about 20 g/L ispreferred.

[0023] Examples of magnesium ion sources include magnesium hydroxide,magnesium carbonate, magnesium acetate, magnesium halides, magnesiumoxide, magnesium nitrate, magnesium phosphate, and the like. Magnesiumhydroxide is preferred. Similarly, examples of calcium ion sourcesinclude calcium hydroxide, calcium carbonate, calcium acetate, calciumhalides, calcium oxide, calcium nitrate, calcium phosphate, and thelike. Calcium hydroxide is preferred.

[0024] Examples of phosphate ion sources include ammonium phosphates,calcium phosphates, magnesium phosphates, Group I phosphates such aspotassium and sodium phosphates, and the like. A water-soluble phosphateion source is preferred, with diammonium hydrogen phosphate beingparticularly preferred.

[0025] Hydroxide ion sources include hydroxide-containing compounds suchas ammonium hydroxide, calcium hydroxide, magnesium hydroxide, sodiumhydroxide, potassium hydroxide, and the like, and compounds thatgenerate hydroxide ion in aqueous solution, such as ammonia, calciumoxide, magnesium oxide, and the like.

[0026] Depending upon the end-use application, other ion sources may beincluded as well, of a quality and quantity that do not disrupt thehydroxyapatite lattice structure. Thus, quantities of source materialsmay be employed that introduce up to about 25 wt % into the Mg—HAplattice structure, depending upon the ions, of one or more cations, forexample, sodium, lithium, barium, strontium, zinc, cadmium, lead,vanadium, silicon, germanium, iron, arsenic, manganese, aluminum, rareearth elements, cobalt, silver, chromium, antimony, and the like, or oneor more anions, for example, carbonate, halides, oxygen, sulfur and thelike. Suitable additional ion sources and appropriate quantities thereofare readily determined by those of ordinary skill in the art withoutundue experimentation.

[0027] Preferably, at least one ion source is water-insoluble or reactsto form an insoluble apatite phase precursor. This provides a substratemedium for the application of mechanochemical force at the same timethat the hydrothermal process steps are being carried out.

[0028] Stoichiometric quantities of the ion sources are employed,selected to provide the desired ratio of individual HAp latticecomponents, especially the ratio of calcium to magnesium and the rationcations occupying the calcium sites to phosphorous. Water-soluble ionsources are dissolved in the aqueous reaction medium, with a slurrybeing formed of the non-water-soluble ion sources. The preferred aqueousmedium is essentially pure distilled water, that more preferably hasbeen deionized and/or demineralized. Up to about 40 wt % of the combinedamounts of the ion sources may be added to the aqueous reaction medium,at a temperature maintained between about 8 and 35° C., and preferablybetween about 25 and about 35° C., until Mg—HAp is formed. Externalsources of heat are not needed, with sufficient heat being supplied bymilling friction. Instead, external cooling may be needed because themolecular activation of the slurry can generate local zones of hightemperature (up to 450-700° C.) and corresponding pressures due tofriction and adiabatic heating of gas bubbles.

[0029] With stirring of the aqueous slurry/solution, the ion sources aremechanochemically reacted, typically by the application of physicalforce to the water-insoluble ion sources or insoluble apatite precursorsthat are suspended as a slurry in the aqueous reaction medium containingthe water-soluble ion sources. Preferred mechanochemical reactionprocesses comminute the ion source slurry particles, preferably bymilling or grinding the water insoluble ion source particles withheating of the aqueous reaction medium into which the water-soluble ionsource has been dissolved. Preferred methods at the same timefrictionally heat the aqueous reaction medium/slurry while the slurryparticles are being milled or ground, so that the mechanochemical andhydrothermal process step are performed simultaneously.

[0030] Multi-ring media mills are preferred. The grinding mechanismconsists of a central rotating stainless steel shaft, which drives aplurality of stainless steel sub-shafts (sleeve-lined withzirconia-toughened alumina) that are connected symmetrically to thecentral shaft. Each sub-shaft contains a plurality of stacked zirconiarings, which rotate eccentrically around each sub-shaft. When thecentral shaft is rotating, the zirconia rings on the sub-shafts aremoved by the centrifugal force radially outwards, applying force on theinner wall of the milling vessel, which is ceramic lined. Solid slurryparticles located between the rotating rings and the liner wall areconsequently comminuted.

[0031] The comminuting step is performed at rotation speeds between 800and 1500 r.p.m. (for the multi-ring media mill), or higher for highersolid content slurries for at least 1 hour, and preferably from betweenabout 1 and about 10 hours, with the temperature of the aqueous slurrymaintained between about 25 and about 35° C. for the duration. The solidphase is then recovered and washed with distilled water, preferablyrepeatedly. The solid phase is then once again isolated and excess wateris removed, preferably by first centrifuging the material followed byoven drying at a temperature between about 40 and 200° C. Lyophilizationmay also be employed to remove excess water. If desired, dry grindingmay be performed to reduce the powder particle size.

[0032] The inventive method advantageously employs environmentallybenign ion sources in an aqueous reaction medium at mild temperatures.The elevated temperatures associated with prior art calcinationprocesses are thereby avoided.

[0033] When all of the ion sources are water-soluble a solution-phasereaction is first performed, followed by heating to drive off theaqueous phase to recover a powder material that is milled while wetthrough to dryness to complete the mechanochemical reaction. However, aslurry-based reaction is preferred in which one of the ion sources iswater-insoluble. Or two water-soluble material may be employed that forman insoluble apatite precursor that is then milled while wet through todryness to complete the mechanochemical reaction. Under certaincircumstances understood by those skilled in the art, Mg—HAp's ofpresent invention may be produced solely by dry milling.

[0034] With water-insoluble magnesium ion sources, such as magnesiumhydroxide, magnesium oxide, magnesium phosphates, and the like, forhigher levels of magnesium substitution, unreacted quantities of themagnesium ion source will remain that have to be removed by selectivewashing of the Mg—HAp. In a particularly preferred embodiment, theMg—HAp is washed with ammonium citrate aqueous solution, into which theunreacted magnesium ion source will preferentially dissolve. After thiswashing step, the purified Mg—HAp is washed, preferably repeatedly, withdistilled water and then dried.

[0035] In a preferred procedure Mg—HAp powders are prepared bysuspending a mixture of calcium hydroxide and magnesium hydroxidepowders in water and subsequently adding a s soluble diammonium hydrogenphosphate powder, quantities as required by stoichiometry. Themechanochemical-hydrothermal synthesis is then performed by placing theslurry into a multi-ring media mill and then grinding the slurry. Theresulting powder is washed using water to remove soluble salts with anammonium citrate aqueous solution washing step performed first forreactions employing higher levels of magnesium substitution. Followingthe water washing, the Mg—HAp is then dried.

[0036] The inventive method provides crystalline Mg—HAp powders in whichat least 75 wt % of the magnesium content is substituted for calciumions in the hydroxyapatite lattice structure. Crystalline Mg—HAp inwhich essentially all of the magnesium content is substituted forcalcium ions in the hydroxyapatite lattice structure can be readilyobtained without undue effort. Accordingly, substitution levels betweenabout 80 wt % and 98 wt % can be readily obtained by the ordinarilyskilled artisan following the teachings of the present specification.

[0037] The crystalline Mg—HAp will have a magnesium content betweenabout 2.0 and about 29 wt %, with levels between about 3.5 and about28.4 wt % being preferred. Levels between about 5 and about 25 wt % areeven more preferred, with a level of at least 10 wt % being mostpreferred. The crystalline Mg—HAp of the present invention formscrystals agglomerates having an approximate particles ranging in sizebetween about 5 nm and about 10 microns.

[0038] The crystalline Mg—HAp of the present invention is useful in thepreparation of compounds for use as granular fill for directincorporation into the hard tissues of humans or other animals, and asbone implantable materials. The present invention thus includes granularfill compounds, bone implant materials, tooth filling compounds, bonecements and dentifrices containing the Mg—HAp of the present invention.The products are formulated and prepared by substituting the Mg—HAp ofthe present invention for HAp in conventional HAp-based products. Thecompounds may be prepared from metallic and polymeric Mg—HAp composites.

[0039] The Mg—HAp of the present invention may also be substituted forthe HAp in support materials for gas sensors and chromatography columns.It may also be substituted for HAp and other support substrates andhosts in catalytic supports, plant growth substrates and in hostmaterials for luminescent applications. Therefore, the present inventionalso includes packing materials for chromatography columns and gassensors, catalytic supports, plant growth substrates and host materialsfor luminescent applications containing the Mg—HAp of the presentinvention.

[0040] The following non-limiting examples set forth herein belowillustrates certain aspects of the invention. All parts and percentagesare by weight unless otherwise noted and all temperatures are in degreesCelsius. Stoichiometric values in HAp and Mg—HAp formulas areapproximate.

EXAMPLES Example 1

[0041] Mechanochemical-hydrothermal synthesis of Ca₈Mg₂(PO₄)₆(OH)₂.

[0042] Calcium hydroxide, magnesium hydroxide and solid diammoniumhydrogen phosphate (analytical grade, Alfa Aesar, Ward Hill, Mass.) wereused as reactants for the synthesis of Mg—HAp. First, a suspensioncontaining a powder mixture of 22.170 g calcium hydroxide and 4.557 gmagnesium hydroxide in 350 mL deionized water was prepared inside a 500ml glass beaker. Subsequently, 29.410 g of diammonium hydrogen phosphatepowder was slowly added to the same beaker at constant vigorous stirringusing a magnetic stirrer for about 10 minutes. The (Ca+Mg)\P molar ratioin the starting slurry was 1.67. The presence of water adsorbed on allreactants was measured by thermogravimetry to maintain the targetedstoichiometry. The pH of the slurry was about 10.3, measured using aglass electrode connected to a small pH-meter (ACCUMET™ Model 805 MP,Fisher Scientific, Pittsburgh, Pa.) and calibrated with respect to abuffer solution (pH=10.00, Fisher Scientific). Themechanochemical-hydrothermal synthesis was performed by placing theslurry into a laboratory scale mill (Model MIC-0, NARA Machinery Co.,Tokyo, Japan) equipped with a zirconia liner and a zirconia ringgrinding media. Grinding of the slurry was carried out in air, initiallyat a rotation speed of 1500 rpm for one hour and then at 800 rpm forfour hours. Temperature during the grinding was measured using athermocouple and determined to be 33° C. at 1500 rpm and 28° C. at 800rpm.

[0043] Washing of the solid phase after the mechanochemical-hydrothermalsynthesis was accomplished by four cycles of shaking the solid withdistilled water in 250 mL HDPE bottles using a hand shaker machine ModelM37615, Barnstead/Thermolyne, Dubuque, Iowa) followed by centrifuging at4500 rpm for 30 minutes (Induction Drive Centrifuge, Model J2-21M,Beckman Instruments, Fullerton, Calif.). The washed solid phase wasdried in an oven at 70° C. for 24 hours (ISOTEMP™ Oven, Model 230GFisher Scientific) and ground into powder.

[0044] The synthesized Mg—HAp powder contained a fraction of unreactedmagnesium hydroxide. Therefore, it was suspended in a 0.2 M ammoniumcitrate aqueous solution. The ammonium citrate solution was prepared ina 200 mL glass beaker by dissolving 3.843 g of solid citric acid(reagent grade, Aldrich, Milwaukee, Wis.) in 100 mL of distilled waterand subsequently slowly adding ammonia solution (reagent grade, FisherScientific) to yield a pH between 8 and 10. 1.0 g of the Mg—HApcontaining unreacted magnesium hydroxide was then suspended in thesolution. The dissolution of the magnesium hydroxide was accomplishedunder a vigorous stirring using a magnetic stirrer for 12 hours, afterwhich the prior distilled water washing, centrifuging and drying stepswere repeated.

[0045] Phase pure crystalline Mg—HAp essentially free of unreactedmagnesium hydroxide and having a magnesium content of approximately 10wt % in which essentially all of the magnesium content was substitutedfor calcium ions in the hydroxyapatite lattice structure was confirmedby x-ray defraction, Fourier Transform Infra-Red spectroscopy,thermogravimetric analysis and chemical analysis.

[0046] Dynamic light scattering revealed the particle size distributionof the Mg—HAp to be between about 130 and about 2100 nm with a specificsurface area of about 129 m²/g, indicating agglomeration. ScanningElectron Microscopy confirmed agglomerates of nanosized Mg—HAp crystals.

Example 2

[0047] Mechanochemical-hydrothermal synthesis of Ca₇Mg₃(PO₄)₆(OH)₂

[0048] Ca(OH), MG(OH)₂ and solid (NH₄)₂HPO₄ (analytical grade, AlfaAesar, Ward Hill, Mass.) were used as reactants for the synthesis ofMg—HAp. First, a suspension containing a powdered mixture of 19.150 gCa(OH)₂ and 6.717 g Mg(OH)₂ in 350 mL of deionized water was preparedinside a 500 mL glass beaker. Subsequently, 29.028 g of (NH₄)₂HPO₄powder was slowly added to the same beaker at constant vigorous stirringusing a magnetic stirrer for about 10 min. The (Ca+Mg)\P molar ratio inthe starting slurry was 1.67. The presence of water adsorbed on allreactants was measured by thermogravimetry to maintain the targetedstoichiometries. The pH of the slurry was about 10.2, measured using aglass electrode connected to a pH-meter (Accumet Model 805 MP, FisherScientific, Pittsburgh, Pa.) and calibrated with respect to a buffersolution (pH=10.00, Fisher Scientific).

[0049] The mechanochemical-hydrothermal synthesis was performed byplacing the slurry into a laboratory-scale mill (model MIC-0, NARAMachinery Co., Tokyo, Japan) equipped with a zirconia liner and zirconiaring grinding media. Grinding of the slurry was carried out in air,initially at a rotation speed of 1500 rpm for 1 h and then at 800 rpmfor 4 h. Temperature during the grinding was measured using athermocouple and was determined to be 33° C. at 1500 rpm and 28° C. at800 rpm. Washing of the solid phase after themechanochemical-hydrothermal synthesis was accomplished by 2-6 cycles ofshaking the solid with distilled water in 2-6 HDPE 250 mL bottles usinga hand shaker machine (Model M37615, Barnstead/Thermolyne, Dubuque,Iowa) followed by centrifuging at 4500 rpm for 30 min. (Induction DriveCentrifuge, Model J2-21M, Beckman Instruments, Fullerton Calif.).

[0050] The washed solid phase was dried in an oven at 70° C. for 24 h(Isotemp oven, model 230G, Fisher Scientific) and ground into powder.The synthesized MG—HAp powder contained a fraction of unreacted Mg(OH)2.Therefore, it was suspended in 0.2 M-ammonium citrate aqueous solution.The ammonium citrate solution was prepared in a 250 mL glass beaker bydissolving 3.843 g of solid citric acid (reagent grade, Aldrich,Milwaukee, Wis.) in 200 mL of distilled water and subsequently slowlyadding ammonia solution (reagent grade, Fisher Scientific) to yield a pHof 10. 1.0 g of the Mg—HAp containing unreached Mg(OH)₂ was thensuspended in the solution. The dissolution of the Mg(OH)₂ wasaccomplished under a vigorous stirring using a magnetic stirrer for 24h. This procedure was repeated once under the same conditions, in orderto completely remove the Mg(OH)₂ phase.

[0051] Properties: Mg content: 15 wt %, particle size distribution:250-4500 nm, SSA: 115 m²/g.

COMPARATIVE EXAMPLE

[0052] Example 1 was repeated substituting 2-propanol (C₃H₇OH,histological grade, Fisher Scientific) for water, so that the reactionconditions were purely mechanochemical. Under otherwise equivalentconditions, no Mg—HAp was observed to form. This emphasizes theimportance of the hydrothermal conditions provided by the aqueousreaction medium in which at least one of the ion sources is soluble, andwhich thus actively participates in the synthesis reaction by dissolvingone of the reactants.

[0053] The present invention thus provides for the reproducible andlow-cost fabrication of high-quality Mg—HAp powders in large batchsizes. The foregoing examples and description of the preferredembodiment should be taken as illustrating, rather than as limiting thepresent invention as defined by the claims. As will be readilyappreciated, numerous variations and combinations of the features setforth above can be utilized without departing from the present inventionas set forth in the claims. Such variations are not regarded as adeparture from the spirit and scope of the invention, and all suchvariations are intended to be included within the scope of the followingclaims.

What is claimed is:
 1. A stable, phase-pure magnesium-substitutedcrystalline hydroxyapatite comprising from about 2.0 to about 29 wt %magnesium, wherein at least 75 wt % of the magnesium content issubstituted for calcium ions in the hydroxyapatite lattice structure. 2.The phase-pure magnesium-substituted crystalline hydroxyapatite of claim1, comprising from about 3.5 to about 28.4 wt % magnesium.
 3. Thephase-pure magnesium-substituted crystalline hydroxyapatite of claim 2,comprising from about 5 to about 25 wt % magnesium.
 4. The phase-puremagnesium-substituted crystalline hydroxyapatite of claim 1, whereinessentially all of the magnesium content is substituted for calcium ionsin the hydroxyapatite lattice structure.
 5. The phase-puremagnesium-substituted crystalline hydroxyapatite of claim 1, comprisingcrystal agglomerates having a particle size between about 5 nm and about100 microns.
 6. A method for the preparation of phase-pure crystallinemagnesium-substituted hydroxyapatite comprising mechanochemicallyreacting a source of calcium ions, a source of magnesium ions, a sourceof phosphate ions and a source of hydroxide ions, at least one of whichis soluble in water, in a aqueous reaction medium until said magnesiumsubstituted-hydroxyapatite is formed.
 7. The method of claim 6, whereinsaid ion sources are stoichiometrically selected to provide apredetermined level of magnesium substitution.
 8. The method of claim 6,further comprising the step of separating said magnesium-substitutedhydroxyapatite from said aqueous reaction medium.
 9. The method of claim8, further comprising the step of washing said magnesium-substitutedhydroxyapatite with water.
 10. The method of claim 9, further comprisingthe step of drying said magnesium-substituted hydroxyapatite.
 11. Themethod of claim 9, further comprising the step of washing saidmagnesium-substituted hydroxyapatite with an aqueous ammonium citratesolution before washing said magnesium-substituted hydroxyapatite withwater.
 12. The method of claim 6, wherein at least one of the ionsources is water-insoluble.
 13. The method of claim 12, wherein thecalcium ion source or the magnesium ion source is water-insoluble. 14.The method of claim 6, wherein said phosphate ion source is watersoluble.
 15. The method of claim 6, wherein said magnesium ion source isselected from the group consisting of magnesium hydroxide, magnesiumcarbonate, magnesium halides, magnesium oxide, magnesium nitrate andmagnesium phosphate.
 16. The method of claim 15, wherein said magnesiumion source is magnesium hydroxide.
 17. The method of claim 6, whereinsaid calcium ion source is selected from the group consisting of calciumhydroxide, calcium carbonate, calcium halides, calcium oxide, calciumnitrate and calcium phosphate.
 18. The method of claim 17, wherein saidcalcium ion source is calcium hydroxide.
 19. The method of claim 6,wherein said phosphate ion source is selected from the group consistingof ammonium phosphates, calcium phosphates, magnesium phosphates, andsodium phosphates.
 20. The method of claim 19, wherein said phosphateion source is diammonium hydrogen phosphate.
 21. A packing material foruse in a chromatography column or gas sensor or as a catalytic supportcomprising the magnesium-substituted hydroxyapatite of claim
 1. 22. Abiocompatible hard tissue implant comprising the magnesium-substitutedhydroxyapatite of claim
 1. 23. The biocompatible hard tissue implant ofclaim 22, comprising a metal or polymeric implant coated with saidmagnesium-substituted hydroxyapatite.
 24. The biocompatible hard tissueimplant of claim 22, comprising a polymeric composite.
 25. A granularfill for direct incorporation into human or animal tissues comprisingthe magnesium-substituted hydroxyapatite of claim
 1. 26. The granularfill of claim 25, comprising a metal or polymeric composite for fillingdental cavities.
 27. A plant growth substrate comprising themagnesium-substituted hydroxyapatite of claim
 1. 28. A dentifricecomposition comprising the magnesium-substituted hydroxyapatite ofclaim
 1. 29. A method for increasing the magnesium content in thelattice structure of magnesium-substituted crystalline hydroxyapatiterelative to the calcium content of the lattice structure and to thenon-lattice magnesium content, said method comprising washing saidmagnesium-substituted hydroxyapatite with an aqueous ammonium citratesolution.
 30. A host material for luminescent applications comprisingthe magnesium-substituted hydroxyapatite of claim 1.